Each Tracidol Prolonged Release Capsule 100 mg contains Tramadol Hydrochloride 100 mg.
Pharmacology: (Summary of Pharmacodynamics and Pharmacokinetics): Tramadol is a centrally acting analgesic. Tramadol is a non-selective, pure agonist in the μ, and K opiate receptors, and it attaches itself most effectively to the μ-receptor. Other factors that contribute to its analgesic effects are inhibition of neuronal re-uptake of noradrenaline and enhancement of 5-HT release.
Tramadol has an antitussive effect. In opposition to morphine, analgesic doses of tramadol do not produce respiratory depression during a wide interval. Tramadol does not affect to gastrointestinal motility and its effects on the cardiovascular system are mild. The potency of tramadol is 1/10-1/6 of that of the morphine.
Antinociceptive efficacy of TRACIDOL has been shown with osteoarthritis patients.
Absorption: Tramadol is absorbed almost completely when administered orally, and the absolute efficiency is approximately 70%. Tramadol metabolises into O-desmethyl Tramadol, which has proven to have an analgesic effect in rodents. The half-life elimination of Tramadol is approximately 6 hours. The half-life increases, however, to 9 with the capsules of TRACIDOL due to the long absorption time.
When a single capsule of 200 mg of TRACIDOL was given to a fasting patient, the average maximum content concentration of the plasma (Cmax) achieved was 299.59 ng·ml-1 (in the interval 240-300 ng/ml). A median Tmax 9.59 hours (9-12 hours) was related to this. After the dosage had been adapted, the efficiency of Tramadol produced by a capsule of TRACIDOL of 200 mg was complete, in comparison with 50 mg of immediately liberated Tramadol. In the presence of food, the availability and controlled release properties of TRACIDOL capsules were maintained, with no evidence of dose dumping. In addition, a steady state study has shown that the capsule of 200 mg of TRACIDOL has a comprehensive systemic predisposition that corresponds to an immediately absorbed product, (immediate release capsule 50 mg). The scatter of the patients participating in the study was not superior to that of the reference group.
Distribution: Tramadol has a high tissue affinity with an apparent volume of distribution of 203 ± 40 litres after oral dosing in healthy volunteers. Protein binding is limited to 20%.
Biotransformation: In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half-life t½β (6 healthy volunteers) is 7.9 h (range 5.4-9.6 h) and is approximately that of tramadol. The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of any such interactions are not known.
Elimination: Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively have been determined. In patients with renal insufficiency (creatinine clearance <5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h, respectively.
Linearity/non-linearity: Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range. A single dose-proportionality study has confirmed a linear pharmacokinetic response (in relation to tramadol and O-desmethyltramadol) following administration of the 100 mg, 150 mg and 200 mg capsules.
The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100 - 300 ng/ml is usually effective.
Treatment of moderate to severe pain.
TRACIDOL capsules should be administered every 24 hours. The capsules should be swallowed whole without chewing. The dosage of Tramadol is determined by the severity of the pain and according to the clinical response of the individual patient. This is valid for all pain relief medicinal products. The correct individual dosage is one that relieves the pain for 24 hours without having any side effects or having side effects of a tolerable level. Patients switched from immediate release tramadol preparations should have their total daily dose calculated, and start on the nearest dose in the TRACIDOL range. It is recommended that patients are slowly titrated to higher doses to minimise transient side effects. TRACIDOL should under no circumstances be administered for longer than is strictly necessary. If repeated use or long-term treatment with tramadol is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible), to assess whether continuation of the treatment is necessary.
The daily total dosage must not exceed 400 mg, unless clinical exceptional circumstances require this.
Dosing in special patients groups: Adults and children over 12 years: The usual starting dosage is one capsule of 100-200 mg per day. If this dosage does not relieve the pain, the dosage is to be raised until an effect of pain relief has been attained.
Elderly people: Patients under 75 years of age with normal liver and kidney functions can be given the normal dosage for adults. In patients over 75 years of age the half-life of Tramadol is prolonged. For those patients, an adjustment of the dosage may be required. If the dosage is increased the condition of the patient must be closely monitored.
Patients with renal insufficiency: The elimination of Tramadol may be delayed. Tramadol is not recommended for patients suffering from moderate to severe kidney insufficiency (creatinine clearance <30 ml/min).
Patients with hepatic insufficiency: Tramadol is contra-indicated in patients with severe hepatic insufficiency. In patients with moderate hepatic insufficiency, tramadol is not recommended.
Children under 12 years: Not recommended.
Mode of Administration: Oral administration.
Symptoms: Also for other opioid analgesics the typical symptoms of overdose are miosis, emesis, cardiovascular collapse, sedation and coma, seizures and respiratory depression.
Treatment: Supportive action should be taken: the respiratory tract should be kept open and the cardiovascular functions should be supported. In case of respiratory depression naloxone may be used in resuscitation. The convulsions can be controlled with diazepam.
Tramadol is minimally eliminated from the serum via haemodialysis or blood filtering. For this reason it is not sufficient to perform only haemodialysis or blood filtering for the treatment of acute Tramadol intoxication.
The removal of the unabsorbed drug by gastric emptying is useful; particularly when a modified release formulation has been taken.
Tramadol Hydrochloride is contraindicated in: Hypersensitivity to Tramadol or to or to any of the excipients of the medicinal product.
Acute intoxication with alcohol, hypnotics drugs, centrally acting analgesics, opioids or psychotropic drugs.
Tramadol should not be administered to patients who are receiving monoamine oxidase (MAO) inhibitors or within two weeks of their withdrawal.
Severe hepatic insufficiency.
Epilepsy not controlled by treatment.
Breast-feeding, if long term treatment is necessary.
In severe respiratory insufficiency, tramadol is not recommended.
Tramadol is not recommended in patients with moderate and severe renal insufficiency and in patients with moderate hepatic insufficiency.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with tramadol only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit.
Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended.
Tramadol should be used with caution in opioid-dependent patients, or in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problem affecting the respiratory center or the respiratory function, or with an increased intracranial pressure.
At therapeutic doses, tramadol has the potential to cause withdrawal symptoms. Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment should be for short periods under strict medical supervision.
Symptoms of withdrawal reactions, similar to those during opiate withdrawal may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.
At recommended doses tramadol is unlikely to produce clinically relevant respiratory depression. Care should however be taken when administering tramadol to patients with existing respiratory depression or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.
Effects on Ability to Drive and Use Machines: Tramadol may cause drowsiness. Alcohol and other medicinal products, which depress the central nervous system, may increase this effect. If affected, the patient should not drive or operate machinery.
Pregnancy: It is preferable to avoid the use of TRACIDOL during the first trimester of pregnancy. From the second trimester, cautious use is possible, punctually.
In human, there are no sufficient data to assess malformative effect of tramadol when given during first trimester of pregnancy. Animal studies did not show any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity appeared.
As other opioid analgesics: During the first trimester, chronic use of tramadol may induce-for any dosage-a withdrawal syndrome in the newborn. At the end of pregnancy, high dosages-even for short term treatment-may induce respiratory depression in the newborn.
Lactation: About 0.1% of maternal dose of tramadol is excreted into milk. Punctual administration appears to be safe for the newborn. If repeated administration for several days is necessary, breast-feeding should be discontinued.
If long-term treatment after birth is necessary, breast-feeding is contraindicated.
The most commonly reported undesirable effects caused by the medicinal product are nausea and dizziness, which both appear in over 10% of the patients.
Disorders of the digestive system: Very common (>10%): nausea. Common (1-10%): emesis, constipation, drying of the mouth. Uncommon (<1%): vomiting, irritation of the digestive system (sense of pressure in the stomach, bloating). Rare (<0.1%): change in appetite.
Disorders in connection with the heart and arteries: Uncommon (<1%): cardiovascular regulation (palpitation, tachycardia, hypotension in connection with posture or cardiovascular collapse). These undesirable effects may be found especially in patients who are physically over-strained. Rare (<0.1 %): bradycardia, increase in blood pressure.
Disorders of the central and peripheral nervous system: Very common (>10%): dizziness. Common (1-10%): headache, incoherence. Rare (<0.1%): respiratory depression. If the recommended dosages are considerably exceeded and simultaneously given with other compounds that affect the central nervous system, a respiratory depression may occur. Seizures resembling epilepsy occurred mainly after large doses of Tramadol had been administered or when the patient had been simultaneously treated with medicinal products which may reduce the seizure threshold, or, as such, cause cerebral convulsions, numbness, trembling, and changes in appetite.
Psychiatric disorders: Rare (<0.1%): psychic side effects may occur after the administration of Tramadol and there may occur individual variations of the strength and the character of the adverse effects (depending on the personality and the duration of the medication). Changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, sporadically increases) and changes in the cognitive and sensory capabilities (for example decision making, disorders of perception), hallucinations, confusion, sleep disturbances and nightmares.
Very rare (<0.01%): addiction, abuse and withdrawal symptoms may occur. Withdrawal symptoms may be: agitation, anxiety, nervousness, insomnia, hyperkinesias, tremors and disorders of the digestive system.
The majority of these are very similar to those occurring in connection with opiate withdrawal.
Visual disorders: Rare (<0.1%): blurred vision.
Respiratory disorders: Rare (<0.1%): dyspnoea and wheezing.
Exacerbation of asthma has also been reported, although the causality has not been established.
Skin and appendages disorders: Common (1-10%): sweating.
Uncommon (<1%): skin reactions (for example itching, rash, urticaria).
Musculo-Skeletal system disorders: Rare: (<0.1%): motor weakness.
Liver and biliary system disorders: In a few isolated cases an increase in liver enzymes has been reported in connection with a temporary therapeutic use of Tramadol.
Urinary system disorders: Rare (<0.1%): urinary disorders (difficulties in passing urine and urinary retention).
Body as whole: Rare (<0.1%): allergic reactions (for example dyspnoea, bronchospasms, wheezing, angioneurotic oedema and anaphylaxis).
Concomitant use is contra-indicated with: Non-selective MAO inhibitors: Risk of serotoninergic syndrome: diarrhoea, tachycardia, sweating, tremor, confusion, even coma.
Selective-A MAO inhibitors: Extrapolation from non-selective MAO inhibitors: Risk of serotoninergic syndrome: diarrhoea, tachycardia, sweating, tremor, confusion, even coma.
Selective-B-MAO inhibitors: Central excitation, symptoms evocative of a serotoninergic syndrome: diarrhoea, tachycardia, sweating, tremor, confusion, even coma. In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol.
Concomitant use is not recommended with: Alcohol: Alcohol increases the sedative effect of opioid analgesics. The effect on alertness can make driving of vehicles and the use of machines dangerous. Avoid intake of alcohol drinks and medicinal products containing alcohol.
Carbamazepine and other enzyme inducers: Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.
Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine): Decrease of the analgesic effect by blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.
Concomitant use which needs to be taken into consideration: In isolated cases there have been reports of serotoninergic syndrome with a temporal relationship with tramadol intake in combination with other serotoninergic medicines such as selective serotonin re-uptake inhibitors (SSRIs) and triptans. Signs of serotonin syndrome may be for example, confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. The treatment with medicinal products depends on the nature and severity of the symptoms.
Other opioid derivatives (including antitussive drugs and substitutive treatments), benzodiazepines and barbiturates. Increased risk of respiratory depression which can be fatal in cases of overdose.
Other depressants of central nervous system, such as other opioid derivatives (including antitussive drugs and substitutive treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, neuroleptics, centrally-acting antihypertensive drugs, thalidomide and baclofen. These drugs can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous.
As medically appropriate, periodic evaluation of prothrombin time should be performed when tramadol and warfarin like compounds are administered concurrently due to reports of increase INR.
Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite.The clinical importance of such an interaction has not been studied.
Medicinal products reducing the seizure threshold, such as bupropion, serotonin re-uptake inhibitor antidepressants, tricyclic antidepressants and neuroleptics concomitant use of tramadol with these drugs can increase the risk of convulsions.
Store at temperature below 30°C.
Shelf-Life: 18 months.
N02AX02 - tramadol ; Belongs to the class of other opioids. Used to relieve pain.
Cap 50 mg x 50 x 10's. PR cap 100 mg (light blue cap and body containing white pellets) x 30's, 500's, 1000's. Inj (vial) 50 mg/mL x 2 mL x 10's, 50's, 100's.